JP2002193809A - Method for treatment of male menopause - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method and a kit for the treatment of male menopause and diseases relating to male menopause, i.e., gymnecomastia, lipid abnormality, cardiovascular disease, atheroscrelosis, hypogenitalism, benign prostatic hyperplacia and osteoporosis. SOLUTION: Male menopause or relating state is treated by using a combination of an estrogenic agent/antagonist with testosterone.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a male climacteric (andro)
pause), and methods and kits for treating diseases associated with or resulting from male menopause. More particularly, the present invention relates to an estrogen agonist
/ Using combinations of antagonists and testosterone to treat male menopause and related illnesses.

[0002]

BACKGROUND OF THE INVENTION Male menopause (male menopause or male rest)
(also called viropause) is a natural event that commonly occurs in men between the ages of 40 and 55. Menopause is due to a decrease in the level of the hormone testosterone.
When testosterone levels decrease and men enter menopause,
Reduced energy and strength, increased body fat, osteoporosis, depression, intellectual loss, inability to maintain muscle strength, cardiovascular disease, atherosclerosis, reduced libido, reduced orgasmic strength, erectile dysfunction, and irritability Various changes or illnesses will be observed, including increased pain, joint pain and stiffness, especially in the hands and feet. In addition, men who are entering menopause or have already entered menopause can have gynecomastia,
It can develop serum lipid abnormalities (including hypercholesterolemia), decreased vasoreactivity, hypogonadism, and benign prostate hyperplasia.

The present invention provides methods and kits for treating male menopause and diseases associated with male menopause.

[0004]

SUMMARY OF THE INVENTION The present invention provides a male menopause,
To treat gynecomastia, dyslipidemia, cardiovascular disease, atherosclerosis, hypogonadism, benign prostatic hyperplasia, or osteoporosis; or to increase libido; or vascular reactivity in male patients Providing a therapeutically effective amount of an estrogen agonist / antagonist and testosterone to a male patient in need of treatment for said disorder. I do.

[0005] In one preferred embodiment of the method of the present invention, the estrogen agonist / antagonist has the formula I

[0006]

Embedded image Wherein A is selected from CH ₂ and NR; B, D, and E are
It is independently selected from CH and N; Y is, (a) 1 to 3 amino phenyl optionally substituted with substituents independently selected from R ^4; (b) independently from R ⁴ Naphthyl optionally substituted with 1 to 3 substituents selected; (c) C ₃ -C ₈ optionally substituted with 1 to 2 substituents independently selected from R ⁴ cycloalkyl; (d) 1 to 2 amino optionally substituted with a substituent C ₃ -C ₈ cycloalkenyl which is independently selected from ^{R 4; (e) -O -} , - NR 2 -, and -S (O) _n - contain heteroatoms from the group up to two selected consisting of, optionally substituted with 1-3 substituents independently selected from R ⁴ 5
Membered heterocycles containing up to two heteroatoms selected from the group consisting of (f) -O-, -NR ^2- , and -S (O) _n- , independently selected from R ⁴ 6 which may be substituted with 1 to 3 substituents
Or (g) a bicyclic ring system formed by condensing a 5- or 6-membered heterocyclic ring with a phenyl ring, wherein the heterocyclic ring is -O-,-
Containing up to two heteroatoms selected from the group consisting of NR ^2- , and -S (O) _n- , and substituted with 1-3 substituents independently selected from R ⁴ May be;
Z ¹ is (a)-(CH ₂ ) _p W (CH ₂ ) _q- ; (b) -O (CH ₂ ) _p CR ⁵ R ^6- ; (c) -O (CH ₂ ) _p W (CH ₂ ) _q- ; (d) -OCHR ² CHR ^3- ; or (e) -SCHR ² CHR ^3- ;; G is (a) -NR ⁷ R ⁸ ; (b)

[0007]

Embedded image Wherein n is 0, 1, or 2; m is 1, 2, or 3; Z ² is -NH-, -O-, -S-, or -CH _2- ; adjacent may be fused with one or two phenyl rings carbon atom, it may optionally be independently substituted with 1-3 substituents carbon atoms, and nitrogen atom, is selected from R ⁴ chemically suitable substituents may be independently substituted); wherein or (c) 5 to 12 carbon atoms, optionally combined crosslinked or condensed, 1 are independently selected from R ⁴ A bicyclic amine optionally substituted with up to 3 substituents; or Z ¹ and G
Are combined

[0008]

Embedded image W is (a) -CH _2- ; (b) -CH = CH-; (c) -O-; (d) -NR ^2- ; (e) -S (O) _n -; (f)

[0009]

Embedded image (g) -CR ² (OH)-; (h) -CONR ^2- ; (i) -NR ² CO-; (j)

[0010]

Embedded image Or (k) -C≡C-;; R is hydrogen or C ₁ -C ₆ alkyl; R ² and R ³ are independently (a) hydrogen; or (b) C ₁ -C ₄ alkyl; a is; R ⁴ is, (a) hydrogen; (b) halogen; (c) C ₁ -C ₆ alkyl; (d) C ₁ -C ₄ alkoxy; (e) C ₁ -C ₄ acyloxy; (f) C ₁ -C ₄ alkylthio; (g) C ₁ -C ₄ alkylsulfinyl; (h) C ₁ -C ₄ alkylsulfonyl; (i) hydroxy (C ₁ -C ₄ ) alkyl; (j) aryl ( C ₁ -C _{4) alkyl; (k) -CO 2 H;} (l) -CN; (m) -CONHOR; (n) -SO 2 NHR; (o) -NH 2; (p) C 1 -C ₄ alkylamino; (q) C ₁ -C _{4 dialkylamino; (r) -NHSO 2 R;} (s) -NO 2; (t) - aryl; or (u) -OH; a and; R ⁵ and R ⁶ is independently C ₁ -C ₈ alkyl, or together forms a C ₃ -C ₁₀ carbocycle and R ⁷ and R ⁸ are independently (a) phenyl; (b) saturated or C ₃ -C ₁₀ carbocyclic unsaturated; (c) -O -, - N-, and Haitai of up to 2 selected from -S- (D) H;; or (e) C ₁ -C ₆ alkyl; a either, or (f) together with R ⁵ or R ⁶ 3~8 C ₃ -C ₁₀ heterocyclic ring containing B atoms R ⁷ and R ⁸ , in linear or cyclic form, up to three independently selected from C ₁ -C ₆ alkyl, halogen, alkoxy, hydroxy, and carboxy The ring formed by R ⁷ and R ⁸ may be fused to a phenyl ring; e is 0, 1, or 2; m
Is 1, 2, or 3; n is 0, 1, or 2; p is
Is 0, 1, 2, or 3; and q is 0, 1, 2, or 3
Or an optical isomer or geometric isomer of the compound; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or prodrug of the compound.

In another preferred embodiment of the invention, the estrogen agonist / antagonist has the formula (IA)

[0012]

Embedded image (Where G is

[0013]

Embedded image R ⁴ is H, OH, F, or Cl; B and E are CH
Or independently selected from N), or a compound or an optical isomer or geometric isomer of the compound; or a pharmaceutically acceptable salt of the compound, N-oxide,
Esters, quaternary ammonium salts, or prodrugs.

In a further preferred embodiment, the estrogen agonist / antagonist is (-)-cis-6-phenyl-5- [4-
(2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-
Tetrahydro-naphthalen-2-ol or an optical or geometric isomer of the compound; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or prodrug of the compound.

In a further preferred embodiment, the estrogen agonist / antagonist (-)-cis-6-phenyl-5-
[4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,
8-tetrahydro-naphthalen-2-ol is in the form of D-tartrate.

Further, for treating male menopause, gynecomastia, dyslipidemia, cardiovascular disease, atherosclerosis, hypogonadism, benign prostatic hyperplasia, or osteoporosis; or for increasing libido Or provided is a method for maintaining or improving vasoreactivity in a male patient, wherein the method comprises tamoxifen, 4-hydroxy tamoxifen, droloxifene, toremifene, centchroman, idoxifen, 6- ( 4-hydroxy-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -naphthalene-2-
All, [4- [2- (2-aza-bicyclo [2.2.1] hept-2-yl) -ethoxy] -phenyl]-[6-hydroxy-2- (4-hydroxy-phenyl) -benzo [b ] Thiophen-3-yl] -methanone, EM-652, EM-800, GW5638, GW7604, optical or geometric isomer of said compound; and pharmaceutically acceptable salts, N-oxides, esters of said compound Administering a therapeutically effective amount of an estrogen agonist / antagonist and a testosterone selected from the group consisting of: a quaternary ammonium salt, and a prodrug to a male patient in need of treatment for said disorder. .

In addition, to treat male menopause, gynecomastia, dyslipidemia, cardiovascular disease, atherosclerosis, hypogonadism, benign prostatic hyperplasia, or osteoporosis; or to increase libido Or a method for retaining or improving vasoreactivity in a male patient, wherein said method comprises formula V or formula VI

[0018]

Embedded image Wherein, R _1B is, H, OH, -OC (O ) -C 1 -C 12 alkyl (linear or branched), - OC ₁ -C ₁₂ alkyl (linear, branched or cyclic), Selected from halogen, or C ₁ -C ₄ halogenated ethers; R _2B , R _3B , R _4B , R _5B , and R _6B
Is H, OH, -OC (O) -C ₁ -C ₁₂ (straight or branched),-
OC ₁ -C ₁₂ (straight, branched or cyclic), halogen,
Independently selected from C ₁ -C ₄ halogenated ethers, cyano, C ₁ -C ₆ alkyl (straight or branched), or trifluoromethyl; X _A is H, C ₁ -C ₆ alkyl, cyano ,
Nitro, selected from trifluoromethyl, and halogen; s is 2 or 3; Y _A part

[0019]

Embedded imageThen, a) R_7BAnd R_8BIs H; C₁-C₆Alkyl; and CN, C₁-C₆
Alkyl (straight or branched), C₁-C₆Alkoxy (direct
Chain or branched chain), halogen, -OH, -CF_Three, Or -O
CF_ThreePhenyl optionally substituted with; from the group consisting of
Independently selected; or b) R_7BAnd R_8BAnd contains one nitrogen heteroatom.
To form a 5-membered saturated heterocycle, wherein said heterocycle
Is hydrogen, hydroxy, halo, C₁-C_FourAlkyl, toriha
Lomethyl, C₁-C_FourAlkoxy, trihalomethoxy, C₁-C_Four
Acyloxy, C₁-C_FourAlkylthio, C₁-C_FourAlkylsul
Finil, C₁-C_FourAlkylsulfonyl, hydroxy (C₁-C
_Four) Alkyl, -CO_TwoH, -CN, -CONHR_1B, -NH_Two, -NH (C₁-C_Four
Alkyl), -N (C₁-C_FourAlkyl)_Two, -NHSO_TwoR_1B, -NHCO
R_1B, -NO_Two, And 1-3 C₁-C_FourSubstituted with alkyl
Independently selected from the group consisting of optionally substituted phenyl
Optionally substituted with 1-3 substituents; or c) R_7BAnd R_8BAnd contains one nitrogen heteroatom.
To form a 6-membered saturated heterocyclic ring,
Is hydrogen, hydroxy, halo, C₁-C_FourAlkyl, toriha
Lomethyl, C₁-C_FourAlkoxy, trihalomethoxy, C₁-C_Four
Acyloxy, C₁-C_FourAlkylthio, C₁-C_FourAlkylsul
Finil, C₁-C_FourAlkylsulfonyl, hydroxy (C₁-C
_Four) Alkyl, -CO_TwoH, -CN, -CONHR_1B, -NH_Two, -NH (C₁-C_Four
Alkyl), -N (C₁-C_FourAlkyl)_Two, -NHSO_TwoR_1B, -NHCO
R_1B, -NO_Two, And 1-3 C₁-C_FourSubstituted with alkyl
Independently selected from the group consisting of optionally substituted phenyl
Optionally substituted with 1-3 substituents; or d) R_7BAnd R_8BAnd contains one nitrogen heteroatom.
To form a 7-membered saturated heterocyclic ring,
Is hydrogen, hydroxy, halo, C₁-C_FourAlkyl, toriha
Lomethyl, C₁-C_FourAlkoxy, trihalomethoxy, C₁-C_Four
Acyloxy, C₁-C_FourAlkylthio, C₁-C_FourAlkylsul
Finil, C₁-C_FourAlkylsulfonyl, hydroxy (C₁-C
_Four) Alkyl, -CO_TwoH, -CN, -CONHR_1B, -NH_Two, -NH (C₁-C_Four
Alkyl), -N (C₁-C_FourAlkyl)_Two, -NHSO_TwoR_1B, -NHCO
R_1B, -NO_Two, And 1-3 C₁-C_FourSubstituted with alkyl
Independently selected from the group consisting of optionally substituted phenyl
Optionally substituted with 1-3 substituents; or e) R_7BAnd R_8BAnd contains one nitrogen heteroatom.
To form an 8-membered saturated heterocyclic ring,
Is hydrogen, hydroxy, halo, C₁-C_FourAlkyl, toriha
Lomethyl, C₁-C_FourAlkoxy, trihalomethoxy, C₁-C_Four
Acyloxy, C₁-C_FourAlkylthio, C₁-C_FourAlkylsul
Finil, C₁-C_FourAlkylsulfonyl, hydroxy (C₁-C
_Four) Alkyl, -CO_TwoH, -CN, -CONHR_1B, -NH_Two, -NH (C₁-C_Four
Alkyl), -N (C₁-C_FourAlkyl)_Two, -NHSO_TwoR_1B, -NHCO
R_1B, -NO_Two, And 1-3 C₁-C_FourSubstituted with alkyl
Independently selected from the group consisting of optionally substituted phenyl
Optionally substituted with 1-3 substituents; or f) R_7BAnd R_8BAnd contains from 6 to 12 carbon atoms.
Are cross-linked or condensed, and
To form a saturated bicyclic heterocyclic ring containing
The heterocycle is hydrogen, hydroxy, halo, C₁-C_FourArchi
, Trihalomethyl, C₁-C_FourAlkoxy, trihalometh
Kissi, C₁-C_FourAcyloxy, C₁-C_FourAlkylthio, C₁-C_Four
Alkylsulfinyl, C₁-C_FourAlkylsulfonyl, ar
Droxy (C ₁-C_Four) Alkyl, -CO_TwoH, -CN, -CONHR_1B, -NH
_Two, -NH (C₁-C_FourAlkyl), -N (C₁-C_FourAlkyl)_Two, -NHSO_TwoR
_1B, -NHCOR_1B, -NO_Two, And 1-3 C₁-C_FourWith alkyl
Independently from the group consisting of optionally substituted phenyl
1 to 3 selected substituents may be substituted)
The compound shown or an optical isomer of the compound or
Geometric isomer; or pharmaceutically acceptable form of said compound
Salts, N-oxides, esters, quaternary ammonium salts,
Or a prodrug; formula Va below

[0020]

Embedded image A compound represented by (TSE-424) or an optical isomer or geometric isomer of the compound; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or prodrug of the compound; or Formula III
Or Formula IV

[0021]

Embedded image Or an optical isomer or geometric isomer of the compound; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or prodrug of the compound; an estrogen agonist selected from the group consisting of: / Administering a therapeutically effective amount of an antagonist and testosterone to a male patient in need of treatment for said disorder.

Further, for treating male menopause, gynecomastia, dyslipidemia, cardiovascular disease, atherosclerosis, hypogonadism, benign prostatic hyperplasia, or osteoporosis; or for increasing libido Or a kit for maintaining or improving vasoreactivity in a male patient is provided, said kit comprising: a) one or more pharmaceutical compositions comprising an estrogen agonist / antagonist and testosterone; and b) Menopause, gynecomastia, dyslipidemia, cardiovascular disease,
For treating atherosclerosis, hypogonadism, benign prostatic hyperplasia, or osteoporosis, or for administering the pharmaceutical composition to increase libido, or to maintain or improve vascular reactivity. Instructions for use;
including.

In a preferred embodiment of the kit, the estrogen agonist / antagonist is of the formula I

[0024]

Embedded image Wherein A is selected from CH ₂ and NR; B, D, and E are
It is independently selected from CH and N; Y is, (a) 1 to 3 amino phenyl optionally substituted with substituents independently selected from R ^4; (b) independently from R ⁴ Naphthyl optionally substituted with 1 to 3 substituents selected; (c) C ₃ -C ₈ optionally substituted with 1 to 2 substituents independently selected from R ⁴ cycloalkyl; (d) 1 to 2 amino optionally substituted with a substituent C ₃ -C ₈ cycloalkenyl which is independently selected from ^{R 4; (e) -O -} , - NR 2 -, and -S (O) _n - contain heteroatoms from the group up to two selected consisting of, optionally substituted with 1-3 substituents independently selected from R ⁴ 5
Membered heterocycles containing up to two heteroatoms selected from the group consisting of (f) -O-, -NR ^2- , and -S (O) _n- , independently selected from R ⁴ 6 which may be substituted with 1 to 3 substituents
Or (g) a bicyclic ring system formed by condensing a 5- or 6-membered heterocyclic ring with a phenyl ring, wherein the heterocyclic ring is -O-,-
Containing up to two heteroatoms selected from the group consisting of NR ^2- , and -S (O) _n- , and substituted with 1-3 substituents independently selected from R ⁴ May be;
Z ¹ is (a)-(CH ₂ ) _p W (CH ₂ ) _q- ; (b) -O (CH ₂ ) _p CR ⁵ R ^6- ; (c) -O (CH ₂ ) _p W (CH ₂ ) _q- ; (d) -OCHR ² CHR ^3- ; or (e) -SCHR ² CHR ^3- ;; G is (a) -NR ⁷ R ⁸ ; (b)

[0025]

Embedded image Wherein n is 0, 1, or 2; m is 1, 2, or 3; Z ² is -NH-, -O-, -S-, or -CH _2- ; adjacent may be fused with one or two phenyl rings carbon atom, it may optionally be independently substituted with 1-3 substituents carbon atoms, and nitrogen atom, is selected from R ⁴ chemically suitable substituents may be independently substituted); wherein or (c) 5 to 12 carbon atoms, optionally combined crosslinked or condensed, 1 are independently selected from R ⁴ A bicyclic amine optionally substituted with up to 3 substituents; or Z ¹ and G
Are combined

[0026]

Embedded image W is (a) -CH _2- ; (b) -CH = CH-; (c) -O-; (d) -NR ^2- ; (e) -S (O) _n -; (f)

[0027]

Embedded image (g) -CR ² (OH)-; (h) -CONR ^2- ; (i) -NR ² CO-; (j)

[0028]

Embedded image Or (k) -C≡C-;; R is hydrogen or C ₁ -C ₆ alkyl; R ² and R ³ are independently (a) hydrogen; or (b) C ₁ -C ₄ alkyl; a is; R ⁴ is, (a) hydrogen; (b) halogen; (c) C ₁ -C ₆ alkyl; (d) C ₁ -C ₄ alkoxy; (e) C ₁ -C ₄ acyloxy; (f) C ₁ -C ₄ alkylthio; (g) C ₁ -C ₄ alkylsulfinyl; (h) C ₁ -C ₄ alkylsulfonyl; (i) hydroxy (C ₁ -C ₄ ) alkyl; (j) aryl ( C ₁ -C _{4) alkyl; (k) -CO 2 H;} (l) -CN; (m) -CONHOR; (n) -SO 2 NHR; (o) -NH 2; (p) C 1 -C ₄ alkylamino; (q) C ₁ -C _{4 dialkylamino; (r) -NHSO 2 R;} (s) -NO 2; (t) - aryl; or (u) -OH; a and; R ⁵ and R ⁶ is independently C ₁ -C ₈ alkyl, or together forms a C ₃ -C ₁₀ carbocycle and R ⁷ and R ⁸ are independently (a) phenyl; (b) saturated or C ₃ -C ₁₀ carbocyclic unsaturated; (c) -O -, - N-, and Haitai of up to 2 selected from -S- (D) H;; or (e) C ₁ -C ₆ alkyl; a either, or (f) together with R ⁵ or R ⁶ 3~8 C ₃ -C ₁₀ heterocyclic ring containing B atoms R ⁷ and R ⁸ , in linear or cyclic form, up to three independently selected from C ₁ -C ₆ alkyl, halogen, alkoxy, hydroxy, and carboxy The ring formed by R ⁷ and R ⁸ may be fused to a phenyl ring; e is 0, 1, or 2; m
Is 1, 2, or 3; n is 0, 1, or 2; p is
Is 0, 1, 2, or 3; and q is 0, 1, 2, or 3
Or an optical isomer or geometric isomer of the compound; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or prodrug of the compound.

In another preferred embodiment of the kit, the estrogen agonist / antagonist has the formula (IA)

[0030]

Embedded image (Where G is

[0031]

Embedded image R ⁴ is H, OH, F, or Cl; B and E are CH and
N is independently selected from N) or an optical isomer or geometric isomer of the compound; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or It is a drag.

In a further preferred embodiment, the estrogen agonist / antagonist is (-)-cis-6-phenyl-5- [4-
(2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-
Tetrahydro-naphthalen-2-ol or an optical or geometric isomer of the compound; or, alternatively, a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or prodrug of the compound.

In a further preferred embodiment, the estrogen agonist / antagonist is in the form of D-tartrate. In other preferred embodiments of the kit, the kit is a male climacteric, gynecomastia, dyslipidemia, cardiovascular disease,
Useful for treating atherosclerosis, hypogonadism, benign prostatic hyperplasia, or osteoporosis, or for increasing libido, or for maintaining or improving vasoreactivity in male patients Includes one or more useful additional compounds.

In another embodiment of the kit, the estrogen agonist / antagonist is tamoxifen, 4-hydroxy tamoxifen, droloxifene, toremifene,
St. chroman, idoxifen, 6- (4-hydroxy-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -naphthalen-2-ol, [4- [2- (2- Aza-bicyclo [2.
2.1] Hept-2-yl) -ethoxy] -phenyl]-[6-hydroxy-2- (4-hydroxy-phenyl) -benzo [b] thiophen-3
-Ile] -Methanone, EM-652, EM-800, GW5638, GW7604,
Optical or geometric isomers of the compound; and pharmaceutically acceptable salts of the compound, N-oxides,
Esters, quaternary ammonium salts, and prodrugs;
Selected from the group consisting of:

In another preferred embodiment of the kit, the estrogen agonist / antagonist is of the formula V or VI

[0036]

Embedded image Wherein, R _1B is, H, OH, -OC (O ) -C 1 -C 12 alkyl (linear or branched), - OC ₁ -C ₁₂ alkyl (linear, branched or cyclic), Selected from halogen, or C ₁ -C ₄ halogenated ethers; R _2B , R _3B , R _4B , R _5B , and R _6B
Is H, OH, -OC (O) -C ₁ -C ₁₂ (straight or branched),-
OC ₁ -C ₁₂ (straight, branched or cyclic), halogen,
Independently selected from C ₁ -C ₄ halogenated ethers, cyano, C ₁ -C ₆ alkyl (straight or branched), or trifluoromethyl; X _A is H, C ₁ -C ₆ alkyl, cyano ,
Nitro, selected from trifluoromethyl, and halogen; s is 2 or 3; Y _A part

[0037]

Embedded imageThen, a) R_7BAnd R_8BIs H; C₁-C₆Alkyl; and CN, C₁-C₆
Alkyl (straight or branched), C₁-C₆Alkoxy (direct
Chain or branched chain), halogen, -OH, -CF_Three, Or -O
CF_ThreePhenyl optionally substituted with; from the group consisting of
Independently selected; or b) R_7BAnd R_8BAnd contains one nitrogen heteroatom.
To form a 5-membered saturated heterocycle, wherein said heterocycle
Is hydrogen, hydroxy, halo, C₁-C_FourAlkyl, toriha
Lomethyl, C₁-C_FourAlkoxy, trihalomethoxy, C₁-C_Four
Acyloxy, C₁-C_FourAlkylthio, C₁-C_FourAlkylsul
Finil, C₁-C_FourAlkylsulfonyl, hydroxy (C₁-C
_Four) Alkyl, -CO_TwoH, -CN, -CONHR_1B, -NH_Two, -NH (C₁-C_Four
Alkyl), -N (C₁-C_FourAlkyl)_Two, -NHSO_TwoR_1B, -NHCO
R_1B, -NO_Two, And 1-3 C₁-C_FourSubstituted with alkyl
Independently selected from the group consisting of optionally substituted phenyl
Optionally substituted with 1-3 substituents; or c) R_7BAnd R_8BAnd contains one nitrogen heteroatom.
To form a 6-membered saturated heterocyclic ring,
Is hydrogen, hydroxy, halo, C₁-C_FourAlkyl, toriha
Lomethyl, C₁-C_FourAlkoxy, trihalomethoxy, C₁-C_Four
Acyloxy, C₁-C_FourAlkylthio, C₁-C_FourAlkylsul
Finil, C₁-C_FourAlkylsulfonyl, hydroxy (C₁-C
_Four) Alkyl, -CO_TwoH, -CN, -CONHR_1B, -NH_Two, -NH (C₁-C_Four
Alkyl), -N (C₁-C_FourAlkyl)_Two, -NHSO_TwoR_1B, -NHCO
R_1B, -NO_Two, And 1-3 C₁-C_FourSubstituted with alkyl
Independently selected from the group consisting of optionally substituted phenyl
Optionally substituted with 1-3 substituents; or d) R_7BAnd R_8BAnd contains one nitrogen heteroatom.
To form a 7-membered saturated heterocyclic ring,
Is hydrogen, hydroxy, halo, C₁-C_FourAlkyl, toriha
Lomethyl, C₁-C_FourAlkoxy, trihalomethoxy, C₁-C_Four
Acyloxy, C₁-C_FourAlkylthio, C₁-C_FourAlkylsul
Finil, C₁-C_FourAlkylsulfonyl, hydroxy (C₁-C
_Four) Alkyl, -CO_TwoH, -CN, -CONHR_1B, -NH_Two, -NH (C₁-C_Four
Alkyl), -N (C₁-C_FourAlkyl)_Two, -NHSO_TwoR_1B, -NHCO
R_1B, -NO_Two, And 1-3 C₁-C_FourSubstituted with alkyl
Independently selected from the group consisting of optionally substituted phenyl
Optionally substituted with 1-3 substituents; or e) R_7BAnd R_8BAnd contains one nitrogen heteroatom.
To form an 8-membered saturated heterocyclic ring,
Is hydrogen, hydroxy, halo, C₁-C_FourAlkyl, toriha
Lomethyl, C₁-C_FourAlkoxy, trihalomethoxy, C₁-C_Four
Acyloxy, C₁-C_FourAlkylthio, C₁-C_FourAlkylsul
Finil, C₁-C_FourAlkylsulfonyl, hydroxy (C₁-C
_Four) Alkyl, -CO_TwoH, -CN, -CONHR_1B, -NH_Two, -NH (C₁-C_Four
Alkyl), -N (C₁-C_FourAlkyl)_Two, -NHSO_TwoR_1B, -NHCO
R_1B, -NO_Two, And 1-3 C₁-C_FourSubstituted with alkyl
Independently selected from the group consisting of optionally substituted phenyl
Optionally substituted with 1-3 substituents; or f) R_7BAnd R_8BAnd contains from 6 to 12 carbon atoms.
Are cross-linked or condensed, and
To form a saturated bicyclic heterocyclic ring containing
The heterocycle is hydrogen, hydroxy, halo, C₁-C_FourArchi
, Trihalomethyl, C₁-C_FourAlkoxy, trihalometh
Kissi, C₁-C_FourAcyloxy, C₁-C_FourAlkylthio, C₁-C_Four
Alkylsulfinyl, C₁-C_FourAlkylsulfonyl, ar
Droxy (C ₁-C_Four) Alkyl, -CO_TwoH, -CN, -CONHR_1B, -NH
_Two, -NH (C₁-C_FourAlkyl), -N (C₁-C_FourAlkyl)_Two, -NHSO_TwoR
_1B, -NHCOR_1B, -NO_Two, And 1-3 C₁-C_FourWith alkyl
Independently from the group consisting of optionally substituted phenyl
1 to 3 selected substituents may be substituted)
The compound shown or an optical isomer of the compound or
Geometric isomer; or pharmaceutically acceptable form of said compound
Salts, N-oxides, esters, quaternary ammonium salts,
Or a prodrug; formula Va below

[0038]

Embedded image A compound represented by (TSE-424) or an optical isomer or geometric isomer of the compound; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or prodrug of the compound; or Formula III
Or Formula IV

[0039]

Embedded image Or an optical isomer or geometric isomer of the compound; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or prodrug of the compound.

The present invention is directed to methods of treating male menopause and diseases associated with male menopause. The present invention further relates to kits for treating male menopause and diseases associated with male menopause.

The term "andropause" is known to those skilled in the art and relates to a period in which the amount of testosterone is significantly reduced in the life of an adult male. Generally, the amount of stetosterone naturally decreases as men age. Males after puberty are usually around 300
It has a plasma testosterone concentration in the range of ~ 1200 ng / dL. During and after menopause, the amount of testosterone decreases to about 200 to about 300 ng / dL or less. Menopause is sometimes referred to as “male menopause (male me
medical conditions and accidents can also cause a reduction in testosterone levels, which can lead to diseases commonly associated with male menopause. Treatment is also applicable to these illnesses: Male menopause is determined by having the disease associated therewith and / or by reducing testosterone levels.

"Dyslipidemia" includes hypercholesterolemia, high plasma concentrations of low density lipoprotein (LDL), and HDL.
And low plasma concentrations. The person skilled in the art is well aware of lipid levels that can lead to pathological conditions (dyslipidemia). For example, high plasma concentrations of LDL have been associated with an increased risk of developing cardiovascular disease, particularly atherosclerosis. Administration of the estrogen agonist / antagonist and testosterone is effective to maintain the desired lipid levels and to improve unacceptable lipid levels to acceptable levels. During and after menopause, the frequency of lipid abnormalities increases.

Vasoreactivity is related to the ability of a blood vessel to expand and contract after being given a particular stimulus. The ability of blood vessels to respond appropriately to stimuli is important. For example, contraction of a blood vessel during an ischemic event can cause additional ischemia and exacerbate the damage caused by ischemia. During and after menopause, vasoreactivity generally decreases. Administration of an estrogen agonist / antagonist and testosterone is effective in preventing reduced vasoreactivity and in increasing reduced vasoreactivity.

The present invention further relates to increasing libido in men. It is common for men to have a decreased desire for intercourse during and after menopause. Such reduced sexual desire (reduced libido) can be treated by administering an estrogen agonist / antagonist and testosterone. Administration of an estrogen agonist / antagonist and testosterone increases cravings for sexual intercourse.

The present invention further relates to treating gynecomastia using an estrogen agonist / antagonist and testosterone. Gynecomastia is associated with unnecessary enlargement of the male breast. During and after male menopause, one or both of the male breasts may unnecessarily enlarge. Such unwanted expansion can be treated by administering an estrogen agonist / antagonist and testosterone.

The present invention further relates to treating hypogonadism. Hypogonadism is associated with decreased testicular function, which can result in reproductive dysfunction. Hypogonadism occurs during and after menopause, may also occur in young men, and may delay puberty. Various types of hypogonadism, including Kleinfelder syndrome, bilateral orchidism, Leydig cell hypoplasia, Noonan syndrome, myotonic dystrophy, hypopituitarism, Kalman syndrome, and Prader-Willi syndrome And a disease state in which hypogonadism is observed has been confirmed. Hypogonadism can be treated by administering an estrogen agonist / antagonist and testosterone.

The present invention further relates to benign prostatic hyperplasia (BPH)
To treat. BPH causes obstruction of the bladder outlet and is a benign adenomatous hyperplasia of the periurethral prostate. BP
The onset of H increases during and after menopause. BPH can be treated by administering to an affected patient an estrogen agonist / antagonist and testosterone.

The present invention further relates to treating osteoporosis. Osteoporosis is a condition in which bone density is reduced. As bone density decreases, the skeleton becomes weaker and more prone to fracture. Bone density is determined by the rate of bone formation and the rate of bone resorption. In osteoporosis, the rate of bone resorption exceeds the rate of bone formation. Thus, the treatment of osteoporosis involves reducing the rate of bone resorption, increasing the rate of bone formation, or both. During or after menopause, the incidence of osteoporosis increases. Osteoporosis can be treated by administering to an affected patient an estrogen agonist / antagonist and testosterone.

The present invention further relates to treating atherosclerosis. Atherosclerosis is
It is a patchy subintimal thickening of the middle artery and aorta, which may reduce or completely obstruct blood flow. Usually, plaques are known as plaques. What matters is the size of the plaque. Larger plaques impede blood flow. Plaque
In addition to obstructing blood flow, it may rupture itself, forming a blood clot, which may reduce or completely obstruct blood flow. Stroke or myocardial infarction can occur as a result of reduced or disrupted blood flow. The development of atherosclerosis in men increases during and after menopause. Atherosclerosis can be treated by administering an estrogen agonist / antagonist and testosterone to a patient in need of the treatment. The administration of estrogen agonists / antagonists and testosterone is effective in preventing the formation of atherosclerotic plaques, effective in preventing further growth of atherosclerotic plaques, and reducing the rupture of atherosclerotic plaques it can.

The present invention is further directed to treating cardiovascular diseases, including atherosclerosis. Cardiovascular disease primarily relates to conditions affecting the heart, veins, and arteries. One embodiment of cardiovascular disease involves reduced blood flow to various organs. Decreased blood flow is due to many different causes. For example, arteries that transport blood to organs may be obstructed by atherosclerotic plaques or clots. Certain injuries that occur as a result of reduced blood flow are:
Depending on which organ is suffering from decreased blood flow (also known as ischemia). The term myocardial infarction (heart attack) is used if blood flow is reduced enough to cause death of some of the heart tissue. Similarly, a stroke can occur when blood flow to the brain is reduced. Other types of cardiovascular disease include coronary artery disease (related to atherosclerosis of the arteries that supply the heart with blood) and peripheral arterial occlusion (tips such as legs, arms, hands, and feet). Peripheral blood vessel disorders). The incidence of cardiovascular disease increases at and after menopause. Cardiovascular disease can be treated by administering to an affected patient an estrogen agonist / antagonist and testosterone.

[0051] The amount of testosterone in men can be determined by measuring the amount of testosterone in plasma. Since testosterone binds to specific plasma proteins, the amount of testosterone is measured taking into account the testosterone bound to the protein. Testosterone not bound to protein is sometimes called free testosterone. One skilled in the art is familiar with measuring plasma testosterone levels, including testosterone bound to plasma proteins and free testosterone.

"Treat", "treat
t) ”and“ treating ”are preventive
(Eg, prophylactic) / palliative treatment, or the act of taking preventive or palliative treatment.

"Patient" means a male animal, especially a mammal. Preferred patients are men over 50
(Ie, middle-aged men). "Estrogen agonists / antagonists" are compounds that act on some of the same receptors on which estrogen acts, and in some cases reduce or prevent the action of estrogen. Estrogen agonists / antagonists are "selective estrogen receptor modulators"
Also known as (SERM). Estrogen agonists / antagonists may also be referred to as antiestrogens despite exhibiting some estrogenic activity at some estrogen receptors. Thus, estrogen agonists / antagonists are generally referred to as “pure astrogens (pure a
ntiestrogen) ”. Antiestrogens that can also act as agonists are of type
I is called antiestrogen. Type I antiestrogens activate estrogen receptors to bind tightly in the nucleus for extended periods of time, but recruit impaired receptors (Clark, et al., Steroids 1973; 22: 707). , Ca
pony et al., Mol Cell Endocrinol , 1975; 3: 233).

The estrogen agonist / antagonist and testosterone of the present invention can be administered systemically or locally. When used systemically,
Parenteral (e.g., intravenous, subcutaneous,
For delivery by intramuscular, intraperitoneal, intranasal, or transdermal) or enteric (eg, oral and rectal) delivery, the estrogen agonist / antagonist of the present invention is formulated. Intravenous administration can be by a series of injections or by continuous infusion over an extended period of time. Administration by spaced injections or other routes can occur at intervals ranging from once weekly to 1-3 times daily (or more).

Another method of administering the combination compounds of the present invention is to use a topical dosage form. For example, the active agent can be administered to the patient in the form of a cream, ointment, or gel applied to the skin. Alternatively, the active agent can be delivered using a patch applied to the skin.

Preferred estrogen agonists / antagonists of the present invention include the compounds described in US Pat. No. 5,552,412. These compounds have the formula (I)

[0057]

Embedded image Wherein A is selected from CH ₂ and NR; B, D, and E are
It is independently selected from CH and N; Y is, (a) 1 to 3 amino phenyl optionally substituted with substituents independently selected from R ^4; (b) independently from R ⁴ Naphthyl optionally substituted with 1 to 3 substituents selected; (c) C ₃ -C ₈ optionally substituted with 1 to 2 substituents independently selected from R ⁴ cycloalkyl; (d) 1 to 2 amino optionally substituted with a substituent C ₃ -C ₈ cycloalkenyl which is independently selected from ^{R 4; (e) -O -} , - NR 2 -, and -S (O) _n - contain heteroatoms from the group up to two selected consisting of, optionally substituted with 1-3 substituents independently selected from R ⁴ 5
Membered heterocycles containing up to two heteroatoms selected from the group consisting of (f) -O-, -NR ^2- , and -S (O) _n- , independently selected from R ⁴ 6 which may be substituted with 1 to 3 substituents
Or (g) a bicyclic ring system formed by condensing a 5- or 6-membered heterocyclic ring with a phenyl ring, wherein the heterocyclic ring is -O-,-
Containing up to two heteroatoms selected from the group consisting of NR ^2- , and -S (O) _n- , and substituted with 1-3 substituents independently selected from R ⁴ May be;
Z ¹ is (a)-(CH ₂ ) _p W (CH ₂ ) _q- ; (b) -O (CH ₂ ) _p CR ⁵ R ^6- ; (c) -O (CH ₂ ) _p W (CH ₂ ) _q- ; (d) -OCHR ² CHR ^3- ; or (e) -SCHR ² CHR ^3- ;; G is (a) -NR ⁷ R ⁸ ; (b)

[0058]

Embedded image Wherein n is 0, 1, or 2; m is 1, 2, or 3; Z ² is -NH-, -O-, -S-, or -CH _2- ; adjacent may be fused with one or two phenyl rings carbon atom, it may optionally be independently substituted with 1-3 substituents carbon atoms, and nitrogen atom, is selected from R ⁴ chemically suitable substituents may be independently substituted); wherein or (c) 5 to 12 carbon atoms, optionally combined crosslinked or condensed, 1 are independently selected from R ⁴ A bicyclic amine optionally substituted with up to 3 substituents; or Z ¹ and G
Are combined

[0059]

Embedded image W is (a) -CH _2- ; (b) -CH = CH-; (c) -O-; (d) -NR ^2- ; (e) -S (O) _n -; (f)

[0060]

Embedded image (g) -CR ² (OH)-; (h) -CONR ^2- ; (i) -NR ² CO-; (j)

[0061]

Embedded image Or (k) -C≡C-;; R is hydrogen or C ₁ -C ₆ alkyl; R ² and R ³ are independently (a) hydrogen; or (b) C ₁ -C ₄ alkyl; a is; R ⁴ is, (a) hydrogen; (b) halogen; (c) C ₁ -C ₆ alkyl; (d) C ₁ -C ₄ alkoxy; (e) C ₁ -C ₄ acyloxy; (f) C ₁ -C ₄ alkylthio; (g) C ₁ -C ₄ alkylsulfinyl; (h) C ₁ -C ₄ alkylsulfonyl; (i) hydroxy (C ₁ -C ₄ ) alkyl; (j) aryl ( C ₁ -C _{4) alkyl; (k) -CO 2 H;} (l) -CN; (m) -CONHOR; (n) -SO 2 NHR; (o) -NH 2; (p) C 1 -C ₄ alkylamino; (q) C ₁ -C _{4 dialkylamino; (r) -NHSO 2 R;} (s) -NO 2; (t) - aryl; or (u) -OH; a and; R ⁵ and R ⁶ is independently C ₁ -C ₈ alkyl, or together forms a C ₃ -C ₁₀ carbocycle and R ⁷ and R ⁸ are independently (a) phenyl; (b) saturated or C ₃ -C ₁₀ carbocyclic unsaturated; (c) -O -, - N-, and Haitai of up to 2 selected from -S- (D) H;; or (e) C ₁ -C ₆ alkyl; a either, or (f) together with R ⁵ or R ⁶ 3~8 C ₃ -C ₁₀ heterocyclic ring containing B atoms R ⁷ and R ⁸ , in linear or cyclic form, up to three independently selected from C ₁ -C ₆ alkyl, halogen, alkoxy, hydroxy, and carboxy The ring formed by R ⁷ and R ⁸ may be fused to a phenyl ring; e is 0, 1, or 2; m
Is 1, 2, or 3; n is 0, 1, or 2; p is
Is 0, 1, 2, or 3; and q is 0, 1, 2, or 3
And optical isomers and geometric isomers of the compound; and non-toxic pharmacologically acceptable acid addition salts, N-oxides, esters, quaternary ammonium salts, and prodrugs of the compound. It is shown.

US Pat. No. 5,552,412 discloses yet another preferred compound having the formula (IA)

[0063]

Embedded image (Where G is

[0064]

Embedded image R ⁴ is H, OH, F, or Cl; B and E are CH and
N independently selected from N) and optical isomers and geometric isomers of said compound; and non-toxic, pharmaceutically acceptable acid addition salts, N-oxides, esters, quaternary ammoniums of said compound Shown as salt, and prodrug.

A particularly preferred estrogen agonist / antagonist for the methods and kits of the present invention is cis-6- (4-fluoro-
(Phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalen-2-ol; (-)
-Cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalen-2-ol; cis-6-phenyl-5 -[4- (2-Pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalene-
2-ol; cis-1- [6'-pyrrolidinoethoxy-3'-pyridyl] -2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene; 1- (4'-pyrrolidinoethoxy Phenyl) -2- (4 "-
(Fluorophenyl) -6-hydroxy-1,2,3,4-tetrahydroisoquinoline; cis-6- (4-hydroxyphenyl) -5- [4-
(2-Piperidin-1-yl-ethoxy) -phenyl] -5,6,7,8-
Tetrahydro-naphthalen-2-ol; 1- (4'-pyrrolidinoethoxyphenyl) -2-phenyl-6-hydroxy-1,2,3,4-
Tetrahydroisoquinoline; and pharmaceutically acceptable salts of said compounds. (-)-Cis-6-phenyl-5-
[4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,
A particularly preferred salt of 8-tetrahydro-naphthalen-2-ol is D-tartrate.

Another preferred estrogen agonist / antagonist is disclosed in US Pat. No. 5,047,431. These compounds have the following formula (II)

[0067]

Embedded image Wherein R ^1A and R ^2A may be the same or different and are H, methyl, ethyl, or benzyl groups) and optical and geometric isomers of said compounds; and droloxy Shown as pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts, and prodrugs of the compound, including phen.

A further preferred estrogen agonist / antagonist is tamoxifen disclosed in US Pat. No. 4,536,516: (Ethanamine, 2- [4- (1,2-diphenyl-1-butenyl) phenoxy] -N, N-dimethyl , (Z) -2-, 2-hydroxy-
1,2,3-propanetricarboxylate (1: 1)) and other compounds; 4-hydroxy tamoxifen disclosed in U.S. Pat.No.4,623,660 (i.e., having a hydroxy group at the 4-position of the 2-phenyl moiety) Tamoxifen) and other compounds;
U.S. Pat.Nos. 4,418,068, 5,393,763, 5,457,117
No. 5,478,847, and No. 5,641,790: Raloxifene: (methanone, [6-hydroxy-2- (4-hydroxyphenyl) benzo [b] thien-3-yl] [4- [2- (1- Piperidinyl) ethoxy] phenyl]-, hydrochloride) and other compounds; toremifene disclosed in U.S. Patent Nos. 4,696,949 and 4,996,225:
1-butenyl) phenoxy] -N, N-dimethyl-, (Z)-, 2-hydroxy-1,2,3-propynetricarboxylate (1: 1))
And other compounds; centchromans disclosed in U.S. Pat. No. 3,822,287: 1- [2-[[4-(-methoxy-2,2-dimethyl-3-phenyl-chroman-4-yl) -phenoxy] -ethyl ] -Pyrrolidine and other compounds; idoxifen disclosed in US Pat. No. 4,839,155: pyrrolidine, 1-[-[4-[[1- (4-iodophenyl) -2-phenyl-1-butenyl] phenoxy] ethyl] And other compounds; 6- (4-hydroxy-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy)-as disclosed in U.S. Pat.No. 5,487,795.
[Benzyl] -naphthalen-2-ol and other compounds; and [4- [2- (2-aza-bicyclo [2.2.1] hept-2-yl) -ethoxy] disclosed in International Patent Application WO 95/10513. -Phenyl]-[6
-Hydroxy-2- (4-hydroxy-phenyl) -benzo [b] thiophen-3-yl] -methanone and other compounds. Other preferred compounds include GW5638 and GW7604, the synthesis of which are described in "Wilson et al., J. Med. Chem ., 199.
4; 37: 1550-1552 ".

Still other preferred estrogen agonists /
Antagonists include EM-652 [shown in the following formula (III)] and EM-800 [shown in the following formula (IV)]. EM-652 and EM-8
00 and the activity of the various enantiomers
r et al., J. Med. Chem. , 1997; 40: 2117-2122 ".

[0070]

Embedded image

[0071]

Embedded image Still other preferred estrogen agonists / antagonists include Formulas V and VI below

[0072]

Embedded image

[0073]

Embedded image Wherein R _1B is H, OH, C ₁ -C ₁₂ ester (linear or branched), C ₁ -C ₁₂ (linear or branched or cyclic)
Selected from alkyl ethers, halogens, or C ₁ -C ₄ halogenated ethers (including trifluoromethyl ether and trichloromethyl ether); R _2B , R _3B , R _4B ,
R _5B and R _6B are C ₁ -C ₁₂ esters for H, OH and OH
(Straight or branched), C ₁ -C ₁₂ alkyl ether to OH (straight or branched or cyclic), halogen,
Independently selected from C ₁ -C ₄ halogenated ethers (including trifluoromethyl ether and trichloromethyl ether), cyano, C ₁ -C ₆ alkyl (linear or branched), or trifluoromethyl; X _A is, H, C ₁ -C ₆ alkyl,
Selected from cyano, nitro, trifluoromethyl, and halogen; s is 2 or 3; Y _A is a moiety

[0074]

Embedded image(Where R_7BAnd R_8BIs H; C₁-C₆Alkyl; and CN, C₁
-C₆Alkyl (straight or branched), C₁-C₆Alkoxy
(Straight or branched), halogen, -OH, -CF_Three,Also
Is -OCF_ThreePhenyl optionally substituted with; a group consisting of
B) -O-, -NH-, -N (C₁-C_FourAlkyl)-, -N =, and -S
(O)_u-(Where u is an integer from 0 to 2), select from the group
Water containing up to two heteroatoms
Elemental, hydroxy, halo, C₁-C_FourAlkyl, trihalomethi
, C₁-C_FourAlkoxy, trihalomethoxy, C₁-C_FourAcyl
Oxy, C₁-C_FourAlkylthio, C₁-C_FourAlkylsulfini
, C₁-C_FourAlkylsulfonyl, hydroxy (C₁-C_Four) Al
Kill, -CO_TwoH, -CN, -CONHR_1B, -NH_Two, C₁-C_FourAlkyria
Mino, di (C₁-C_Four) Alkylamino, -NHSO_TwoR_1B, -NHCO
R_1B, -NO_Two, And 1-3 C₁-C_FourSubstituted with alkyl
Independently selected from the group consisting of optionally substituted phenyl
Saturated or unsaturated, which may be substituted with 1 to 3 substituents
Sum or partially unsaturated 5-membered heterocycle; c) -O-, -NH-, -N (C₁-C_FourAlkyl)-, -N =, and -S
(O)_u-(Where u is an integer from 0 to 2), select from the group
Water containing up to two heteroatoms
Elemental, hydroxy, halo, C₁-C_FourAlkyl, trihalomethi
, C₁-C_FourAlkoxy, trihalomethoxy, C₁-C_FourAcyl
Oxy, C₁-C_FourAlkylthio, C₁-C_FourAlkylsulfini
, C₁-C_FourAlkylsulfonyl, hydroxy (C₁-C_Four) Al
Kill, -CO_TwoH, -CN, -CONHR_1B, -NH_Two, C₁-C_FourAlkyria
Mino, di (C₁-C_Four) Alkylamino, -NHSO_TwoR_1B, -NHCO
R_1B, -NO_Two, And 1-3 C₁-C_FourSubstituted with alkyl
Independently selected from the group consisting of optionally substituted phenyl
Saturated or unsaturated, which may be substituted with 1 to 3 substituents
Sum or partially unsaturated 6-membered heterocyclic ring; d) -O-, -NH-, -N (C₁-C_FourAlkyl)-, -N =, and -S
(O)_u-(Where u is an integer from 0 to 2), select from the group
Water containing up to two heteroatoms
Elemental, hydroxy, halo, C₁-C_FourAlkyl, trihalomethi
, C₁-C_FourAlkoxy, trihalomethoxy, C₁-C_FourAcyl
Oxy, C₁-C_FourAlkylthio, C₁-C_FourAlkylsulfini
, C₁-C_FourAlkylsulfonyl, hydroxy (C₁-C_Four) Al
Kill, -CO_TwoH, -CN, -CONHR_1B, -NH_Two, C₁-C_FourAlkyria
Mino, di (C₁-C_Four) Alkylamino, -NHSO_TwoR_1B, -NHCO
R_1B, -NO_Two, And 1-3 C₁-C_FourSubstituted with alkyl
Independently selected from the group consisting of optionally substituted phenyl
Saturated or unsaturated, which may be substituted with 1 to 3 substituents
Sum or partially unsaturated 7-membered heterocycle; ande) containing 6 to 12 carbon atoms,
-O-, -NH-, -N (C ₁-C_FourAlkyl)-, -N =, and -S
(O)_u-(Where u is an integer from 0 to 2), select from the group
Water containing up to two heteroatoms
Elemental, hydroxy, halo, C₁-C_FourAlkyl, trihalomethi
, C₁-C_FourAlkoxy, trihalomethoxy, C₁-C_FourAcyl
Oxy, C₁-C_FourAlkylthio, C₁-C_FourAlkylsulfini
, C₁-C_FourAlkylsulfonyl, hydroxy (C₁-C_Four) Al
Kill, -CO_TwoH, -CN, -CONHR_1B, -NH_Two, C₁-C_FourAlkyria
Mino, di (C₁-C_Four) Alkylamino, -NHSO_TwoR_1B, -NHCO
R_1B, -NO _Two, And 1-3 C₁-C_FourSubstituted with alkyl
Independently selected from the group consisting of optionally substituted phenyl
Bicyclic heterocyclic ring optionally substituted by 1 to 3 substituents;
Selected from the above) and the compound
Optical and geometric isomers; and non-toxicity of said compounds
Pharmacologically acceptable acid addition salts, N-oxides,
, Quaternary ammonium salts, and prodrugs
No. 5,998,402, U.S. Pat.No. 5,985,910,
U.S. Patent No. 5,780,497, U.S. Patent No. 5,880,137, and
And TSE424 disclosed in European Patent Application EP 0802183 A1
There are other compounds.

Preferred compounds of the present invention are those wherein R _1B is H
When R _2B is not OH, then R _2B , R
_3B , R _4B , R _5B , and R _6B are H, OH, C ₁ -C ₁₂ for OH
X _A independently selected from an ester, a C ₁ -C ₁₂ alkyl ether to OH, halogen, cyano, C ₁ -C ₆ alkyl, or trihalomethyl (preferably trifluoromethyl);
There, H, C ₁ -C ₆ alkyl, cyano, nitro, selected from trifluoromethyl, and halogen; Y _A partial

[0076]

Embedded imageAnd R_7BAnd R_8BBut H and C₁-C₆Independently selected from alkyl
Selected or-(CH_Two)_wForms a ring with-
Wherein the ring is hydrogen, hydroxy, halo, C₁-C
_FourAlkyl, trihalomethyl, C₁-C_FourAlkoxy, toriha
Lomethoxy, C₁-C_FourAlkylthio, C₁-C_FourAlkylsulf
Inil, C₁-C_FourAlkylsulfonyl, hydroxy (C ₁-C_Four)
Alkyl, -CO_TwoH, -CN, -CONH (C₁-C_Four) Alkyl, -NH_Two,
C₁-C_FourAlkylamino, C₁-C_FourDialkylamino, -NHSO_Two
(C₁-C_Four) Alkyl, -CO (C₁-C_Four) Alkyl, and -NO_TwoOr
Substituted with up to three substituents selected from the group consisting of
Having the general structures V and VI
Compounds and optical and geometric isomers of the compounds;
And non-toxic pharmacologically acceptable acid addition of said compounds
Salts, N-oxides, esters, quaternary ammonium salts, and
And prodrugs.

The ring formed by combining R _7B and R _8B includes an aziridine ring, an azetidine ring, a pyrrolidine ring, a piperidine ring, a hexamethyleneamine ring, and a heptamethyleneamine ring. Not limited.

The most preferred compounds of structural formulas V and VI are R _1B
Is OH; R _2B -R _6B are as defined above;
X _A is, Cl, be NO _2, CN, CF ₃ or CH _3,; Y _A partial

[0079]

Embedded imageAnd R_7BAnd R_8BBut-(CH_Two)_t-(Where t is 4-6
(Which are integers) are linked together to form a ring,
When said ring is hydrogen, hydroxy, halo, C₁-C_FourArchi
, Trihalomethyl, C₁-C_FourAlkoxy, trihalometh
Kissi, C₁-C_FourAlkylthio, C₁-C_FourAlkylsulfini
, C₁-C_FourAlkylsulfonyl, hydroxy (C ₁-C_Four) Al
Kill, -CO_TwoH, -CN, -CONH (C₁-C_Four) Alkyl, -NH_Two, C₁-C
_FourAlkylamino, di (C₁-C_Four) Alkylamino, -NHSO_Two(C
₁-C_Four) Alkyl, -NHCO (C₁-C_Four) Alkyl, and -NO_TwoOr
Substituted with up to three substituents selected from the group consisting of
And the compound and the compound
Optical and geometric isomers of
, Pharmacologically acceptable acid addition salts, N-oxides,
Ter, quaternary ammonium salts, and prodrugs
You.

Another preferred compound is TSE424, which is represented by the following formula (Va).

[0081]

Embedded image The estrogen agonist / antagonist and / or testosterone, when applicable, can be administered in the form of a pharmaceutically acceptable salt. These salts can be readily formed by reacting a compound of the present invention with a suitable acid, as is commonly done in organic chemistry. These salts are usually formed in high yields at moderate temperatures and are often prepared as the last step in a synthesis by simply isolating the compound from a suitable acidic wash. The salt-forming acid is dissolved in a suitable organic or aqueous organic solvent, such as an alkanol, ketone, or ester. On the other hand, if the compound of the present invention is required in free base form, it is isolated from the final basic washing step according to conventional procedures. A preferred method for producing the hydrochloride is to dissolve the free base in a suitable solvent, dry it sufficiently with molecular sieves and then blow in hydrogen chloride gas. A preferred salt of (-)-cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalen-2-ol is D -(-)-Tartrate. Needless to say, where applicable,
The amorphous form of the estrogen agonist / antagonist can be administered.

The expression "pharmaceutically acceptable salts" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts. The expression “pharmaceutically acceptable cationic salts” refers to alkali metal salts (eg, sodium and potassium salts), alkaline earth metal salts
(E.g., calcium and magnesium salts), aluminum salts, ammonium salts, and organic amines (e.g., benzathine (N, N'-dibenzylethylenediamine),
Choline, diethanolamine, ethylenediamine, megramamine (N-methylglucamine), benetamine (N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol), and procaine). (But not limited thereto). The expression "pharmaceutically acceptable acid addition salts" refers to the hydrochloride, besylate (b
esylate), hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, methanesulfonate (mesylate), And salts such as, but not limited to, p-toluenesulfonate (tosylate).

As is well known to those skilled in the art, certain estrogen agonists / antagonists may be of particular stereochemical,
It contains one or more atoms that may be in tautomeric or geometric configuration, thus giving rise to stereoisomers, tautomers, and configuration isomers. All such tautomers, isomers, and mixtures thereof are also included in the present invention. Hydrates and solvates of the compound of the present invention are also included in the present invention.

The invention further relates to isotopically labeled testosterone and / or estrogen agonists / antagonists, which are structurally identical, but wherein one or more atoms have
Replaced by an atom having an atomic weight or mass number different from the atomic weight or mass number normally found in nature). Examples of isotopes that can be introduced into the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus,
Sulfur, fluorine, and chlorine (respectively, ² H, ^{3
H, 13 C, 14 C,} 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 1 8 F, and ³⁶ Cl) is. Compounds of the invention containing the above isotopes and / or other isotopes of other atoms, prodrugs of the compounds, and pharmaceutically acceptable salts of the compounds and the prodrugs are also within the scope of the invention. is there. Certain isotopically-labelled compounds of the present invention (eg, those into which radioactive isotopes such as ³ H and ¹⁴ C have been introduced) are useful in drug assays and / or substrate tissue distribution assays. Tritiated ( ³ H) and carbon-14 ( ¹⁴ C) isotopes are particularly preferred for their ease of preparation and detectability. In addition, deuterium ( ²
Replacement with an isotope such as H) may provide certain therapeutic benefits (e.g., increased in vivo half-life or reduced required dose) due to increased metabolic stability, and is therefore sometimes preferred. There is. The isotope-labeled compounds of the present invention and their prodrugs are generally subjected to procedures known or described in the literature, using readily available isotope-labeled reagents in place of the non-isotopically labeled reagents. Can be manufactured.

As is well known to those skilled in the art, a bioactive compound having an accessible hydroxyl group can be administered in the form of a pharmaceutically acceptable ester. The compounds of the present invention are advantageously administered as esters formed on the hydroxyl group, as will be apparent to those skilled in the pharmaceutical chemistry arts. As is well known in the pharmaceutical chemistry industry,
By appropriate choice of the ester group, the rate or duration of action of the compounds of the present invention can be adjusted.

When the compound of the present invention contains an ester,
Certain ester groups are preferred. Formulas I, IA, II, III,
Estrogen agonists / antagonists, including compounds of IV, V, Va, or VI, may contain ester groups at various positions as defined herein, and these ester groups are represented as -COOR ^9. Where R ⁹ is C ₁ -C ₁₄ alkyl; C ₁ -C ₃ chloroalkyl; C ₁ -C ₃ fluoroalkyl; C ₅ -C ₇ cycloalkyl; phenyl; or C ₁ -C ₄ alkyl, C ₁ -C is a ₄ alkoxy, hydroxy, nitro, chloro, fluoro or tri (chloro or fluoro) phenyl monosubstituted or disubstituted with methyl.

Testosterone can be administered in the form of an ester. Examples of suitable esters include propionate, enanthate, cypionate, and undecanoate.

[0088] As used herein, "therapeutically effective amount" is an amount of a compound or combination compound that is capable of treating a pathological condition. The specific dose of the compound or combination compound to be administered according to the present invention will be determined by the particular circumstances, including, for example, the type of compound to be administered, the route of administration, and the degree of the pathological condition to be treated.

The dose of the compound administered to the patient will vary within a fairly wide range and will be determined according to the judgment of the attending physician. It is important to note that salts (e.g. laurate)
When administered in the form of, the salt forms a moiety with considerable molecular weight, and the dose of the compound needs to be adjusted.

The following doses are for an average human patient weighing about 65 kg to about 70 kg. The skilled artisan can readily determine the required dose for a patient weighing outside the range of 65 kg to 70 kg based on the patient's medical history. All doses described herein are daily doses. Forms other than the free base form (e.g., salts and hydrates)
The calculation of the dose relative to can easily be done by simply examining the ratio of the molecular weights of the free base form and the form.

A typical range for an effective dose rate of an estrogen agonist / antagonist is from about 0.001 mg / day to about 200 mg / day. A preferred rate range is from about 0.010 mg / day to about 100 mg / day. Of course, it is often practical to divide the daily dose of the compound and administer it at various times of the day. However, in some cases, the amount of the compound administered will depend on factors such as the potency of the particular estrogen agonist / antagonist, the solubility of the compound, the formulation used, and the route of administration.

Exogenous testosterone has been administered to men to increase the amount of testosterone. Of the present invention
One important aspect is that the combination of an estrogen agonist / antagonist and testosterone can reduce the dose of testosterone compared to the dose administered when using testosterone alone. Combined with estrogen agonist / antagonist, 1 if not
One-third or at most half the dose of testosterone may be given. It is beneficial to use lower doses of testosterone. Because exogenous testosterone is administered, negative feedback (negat
ive feedback) can suppress endogenous testosterone secretion. In addition, estrogen agonists / antagonists prevent negative feedback by inhibiting estrogen receptors in the brain.
Furthermore, in men, some testosterone is converted to estrogen. Estrogen in men has some undesirable effects, which are prevented by administering estrogen agonists / antagonists. An example of an appropriate dose range for testosterone when used in combination with an estrogen agonist / antagonist is about 1 to about 10 mg / day for subcutaneous administration, and an equivalent is there. The preferred dose range is about
1 to about 4 mg / day.

Formulations are known in the art and include, for example,
“ Remington's Pharmaceutical Sciences , Mack Publis
Hing Company, Easton, Pa., 19th edition (1995) ". Pharmaceutical compositions for use in the present invention are sterile, non-pyrogenic solutions or suspensions, coated capsules. Suppositories, lyophilized powders, subcutaneous patches, or other forms known in the art.

Capsules are made by mixing a compound of the present invention and a suitable diluent and filling the proper amount of the mixture in capsules. Common diluents include inert powdered substances (e.g., various starches, powdered cellulose, especially crystalline and microcrystalline cellulose), sugars (e.g., fructose, mannitol, and sucrose), flour, and similar edible powders and so on.

Tablets are prepared by direct compression, by wet granulation, or by dry granulation. These formulations typically incorporate a diluent, binder, lubricant, and disintegrant in addition to the compound of the present invention. Representative diluents include, for example, various types of starch,
Lactose, mannitol, kaolin, calcium phosphate, calcium sulfate, inorganic salts such as sodium chloride, and powdered sugar. Powdered cellulose derivatives are also useful. Representative tablet binders are substances such as starch, gelatin, and sugars (eg, lactose, fructose, glucose, and the like). Natural and synthetic gums, including gum arabic, alginates, methylcellulose, polyvinylpyrrolidone, and the like, are also suitable.
Polyethylene glycol, ethyl cellulose, and waxes are also useful as binders.

Lubricants may be necessary in tablet formulations to prevent the tablet and punch from sticking in the die. Lubricants are selected from lubricating solids such as talc, magnesium stearate, calcium stearate, stearic acid, and hydrogenated vegetable oils.

Tablet disintegrants are substances that facilitate the disintegration of a tablet so that the tablet releases the compound when wetted. Disintegrants include starch, clay, cellulose,
There are algins and gums, specifically corn starch and potato starch, methyl cellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resin, alginic acid, guar gum, citrus pulp (citrus pulp), and carboxymethyl cellulose And the like. Sodium lauryl sulfate can also be used.

Tablets are used to improve their dissolution properties.
It is often coated with sugar as a flavor or sealant, or with a film-forming protective agent. The compounds of the present invention can also be formulated as chewable tablets using large amounts of a tasty substance, such as mannitol, which is well established in the art.

Where it is desired to administer the compound as a suppository, the general bases can be used.
Cocoa butter is a traditional suppository base, which can be modified by adding a wax to slightly raise its melting point. Water-miscible suppository bases containing polyethylene glycols of various molecular weights are widely used.

Proper formulation may delay or prolong the effectiveness of the compounds of the present invention.
For example, a slowly dissolving pellet of the compound of the present invention can be prepared and incorporated into a tablet or capsule. Such methods can be improved by making pellets with different dissolution rates and filling a mixture of these pellets into capsules. Tablets or capsules can be coated with a film that will resist dissolution for a predictable period of time. Topical formulations can be designed to allow for delayed and / or prolonged transdermal absorption of the compound. Parenteral preparations can be formulated to be active over time by dissolving or suspending the compound of the present invention in an oily or emulsified vehicle, which allows for a very slow dispersion in serum. Become.

The term "prodrug" refers to a compound that is transformed in vivo to produce a compound of the present invention. Conversion occurs by various mechanisms, such as hydrolysis in blood. A description of the use of prodrugs can be found in “T. Higuchi and W. Stella,“ Pro-d
rugs as Novel Delivery Systems, "Vol.14 of the A.
CS Symposium Series "and" Bioreversible Carri
ers in Drug Design , edited by Edward B. Roche, American
Pharmaceutical Association and Pergamon Press, 198
7 ".

For example, if the compound of the present invention has a carboxylic acid function, the prodrug may be (C ₁ -C ₈ ) alkyl, (C ₂ -C ₁₂ ) alkanoyloxymethyl, 4 to 9 carbon atoms. Having 1- (alkanoyloxy) ethyl, 1-methyl-1- (alkanoyloxy)-having 5 to 10 carbon atoms
Ethyl, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having 4 to 7 carbon atoms, 1-methyl-1- (having 5 to 8 carbon atoms Alkoxycarbonyloxy) ethyl, N- (alkoxycarbonyl) aminomethyl having 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl having 4 to 10 carbon atoms, 3-phthalidyl, Four-
Crotonolactonyl, γ-butyrolactone-4-yl, di-
N, N- (C ₁ -C ₂ ) alkylamino (C ₂ -C ₃ ) alkyl (for example α-dimethylaminoethyl), carbamoyl- (C ₁ -C ₂ ) alkyl, N, N-di (C _1- C ₂ ) alkylcarbamoyl- (C ₁ -C ₂ ) alkyl, piperidino (C ₂ -C ₃ ) alkyl, pyrrolidino (C ₂ -C
₃₎ alkyl or morpholino (C ₂ -C ₃₎ may include esters formed by replacing the hydrogen atom of the group a carboxylic acid group such as alkyl.

Similarly, if the compound of the present invention has an alcohol function, the prodrug may be (C ₁ -C ₆ ) alkanoyloxymethyl, 1-((C ₁ -C ₆ ) alkanoyloxy) ethyl, 1- Methyl-1-((C ₁ -C ₆ ) alkanoyloxy) ethyl,
(C ₁ -C ₆ ) alkoxycarbonyloxymethyl, N- (C ₁ -C ₆ )
Alkoxycarbonylaminomethyl, succinoyl, (C
_1- C ₆ ) alkanoyl, α-amino (C ₁ -C ₄ ) alkanoyl,
Arylacyl, α-aminoacyl, or α-aminoacyl-α-aminoacyl (each α-aminoacyl is a naturally occurring L-amino acid, P (O) (OH) ₂ , -P (O) (O (C _1- C ₆₎ alkyl) formed by ₂ or glycosyl (the replacement of the hydrogen atom of the alcohol group with independently selected is] such groups from groups) produced by removing the hemiacetal form of a hydroxyl group of a carbohydrate, be able to.

When the compound of the present invention has an amine function, the prodrug may be R ^X -carbonyl, R ^X O-carbonyl, NR ^X R ^X '-carbonyl, wherein R ^X and R ^X ' are each independently Typically, (C ₁ -C ₁₀ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, or benzyl, or R ^X -carbonyl is a natural α-aminoacyl or a natural α-aminoacyl-natural α-aminoacyl A), -C (OH) C (O) OY ^X (where Y ^X is
H, (C ₁ -C ₆ ) alkyl or benzyl], -C (OY
^X0) Y ^X1 wherein, Y ^X0 is (C ₁ -C ₄₎ alkyl, Y ^X1 is
(C ₁ -C ₆ ) alkyl, carboxy (C ₁ -C ₆ ) alkyl, amino
(C ₁ -C ₄ ) alkyl, mono-N- (C ₁ -C ₆ ) alkylaminoalkyl, or di-N, N- (C ₁ -C ₆ ) alkylaminoalkyl), or -C (Y ^X2 ) ^{YX3 wherein YX2} is H or methyl, and ^YX3 is mono-N- (C ₁ -C ₆ ) alkylamino, di-N,
N- (C ₁ -C ₆ ) alkylamino, morpholino, piperidine-1-
Yl or pyrrolidin-1-yl], etc., and replacing the hydrogen atom in the amine group.

The present invention is further advantageous in that it provides a kit for use by a consumer to treat male menopause and related conditions. The kit of the invention comprises a) one or more pharmaceutical compositions comprising a) an estrogen agonist / antagonist and / or testosterone, and a pharmaceutically acceptable carrier, vehicle, or diluent; and And related conditions, especially to treat gynecomastia, dyslipidemia, cardiovascular disease, atherosclerosis, hypogonadism, benign prostatic hyperplasia or osteoporosis, or increase libido Instructions describing how to use the pharmaceutical composition to maintain or enhance or enhance vasoreactivity. One or more pharmaceutical compositions of the present invention contain an estrogen agonist / antagonist and testosterone. The estrogen agonist / antagonist may be present in the same pharmaceutical composition as testosterone or in another pharmaceutical composition. One important aspect of the present invention is that both testosterone and an estrogen agonist / antagonist are administered to the patient. The kits of the present invention can be made in a variety of ways to achieve these results.

"Kit" used in the present patent application
Include a container for containing the pharmaceutical composition, and a divided bottle or a divided foil packet.
It may further include a divided container such as an oilpacket). Such containers are made from pharmaceutically acceptable substances,
It can be of any conventional shape or form known in the art, such as paper or cardboard boxes; glass or plastic bottles or jars; resealable bags (e.g., placed in different containers). For containing a "refill" of tablets to be extruded); or blister packs containing individual doses to be pushed out of the pack according to the treatment regimen. The container used will depend on the form of the dosage form, for example a conventional cardboard box would not normally be used to hold a suspension.
Two or more containers can be used together in a single package and marketed as a single dosage form. For example, tablets can be contained in a bottle and the bottle can be contained in a box.

One example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used to package pharmaceutical unit dosage forms (eg, tablets and capsules). Blister packs usually consist of a sheet of relatively rigid material, preferably coated with a foil of a transparent material. During the packaging process, depressions are formed in the plastic foil. These recesses may have the size and shape of the individual tablets or capsules to be packed, or may have the size and shape to accommodate multiple tablets and / or capsules to be packed. The tablet or capsule is then placed in the recess and the sheet of relatively rigid material is sealed against the plastic foil on the side of the plastic foil opposite the side on which the recess is formed. This allows the tablets or capsules to be sealed individually or collectively as required in the recess between the plastic foil and the sheet. The strength of the sheet is such that tablets or capsules can be removed from the blister pack by manually applying pressure to the depressions, thereby forming an opening in the sheet at the location of the depressions. The tablets or capsules can be removed through the openings.

A written memorization aid (a written memor)
It is desirable to provide a written aid, wherein the written memory aid is of a type that includes information and / or instructions for a physician, pharmacist, or patient (e.g., a number adjacent to a tablet or capsule). (Where the number corresponds to the date of the prescription plan to have the specified tablet or capsule taken) or in the form of a card containing the same type of information). Another example of such a memory aid is a calendar printed on a card (eg, "1st week, Monday, Tuesday ...," etc., "2nd week, Monday, Tuesday, "Such). Other variations of memory aids will be readily apparent. The "daily dose" to be taken on a given day may be a single tablet or capsule or multiple tablets or capsules.

Another specific embodiment of the kit is a dispenser designed to dispense the daily dose all at once. Preferably, the dispenser is fitted with a memory-aid, so that compatibility with the regimen is further facilitated. One example of such a memory-aid is a mechanical counter that indicates the number of daily doses that have been dispensed. Other examples of such memory-aids have been associated with liquid crystal readings or audible reminder signals, e.g., to read the date when the most recent daily dose was administered and / or to remind when to take the next dose. It is a battery-operated microchip memory.

The kits of the present invention may further comprise, in addition to the estrogen agonist / antagonist and testosterone, one or more additional pharmaceutically active compounds. The additional compound is another estrogen agonist / antagonist or other compound useful for treating male menopause or a condition associated therewith. Additional compounds include estrogen agonists /
The antagonist and / or testosterone can be administered in the same dosage form, or can be administered in different dosage forms. Similarly, the additional compound can be administered at the same time as the estrogen agonist / antagonist and / or testosterone, or at different times.

It should be further noted that the estrogen agonist / antagonist and testosterone can be administered in the same or different dosage forms. Further, even though the estrogen agonist / antagonist and testosterone are incorporated in the same pharmaceutical composition,
Alternatively they may be incorporated into different pharmaceutical compositions and may be administered simultaneously or sequentially in any order. For example, an estrogen agonist / antagonist is administered as a tablet and testosterone is given
It can be administered transdermally by a patch applied to the skin.

All references, including patents and patent applications, cited herein are hereby incorporated by reference. The following protocol is intended to illustrate certain embodiments of the present invention and is not intended to limit the scope of the present invention.

Protocol The relative potency and efficacy of the estrogen agonist / antagonist combination of the present invention and testosterone can be tested by the following procedure.

Effect on Prostate Weight 3 month old male Sprague-Durley rats (Sprague-D
awley rats) receive vehicle (10% ethanol in water), estradiol (30 μg / kg), testosterone (1 mg / kg), or a combination of estrogen agonist / antagonist and testosterone daily by subcutaneous injection for 14 days I do. After 14 days, the rats are sacrificed, the prostate is removed, and the wet prostate is weighed. Mean weights are determined and statistical significance is determined by comparison with the vehicle-treated group using the Student's tea (t) test.

Bone Mineral Density Bone mineral density (a measure of bone mineral content) is 80% of bone strength.
Dominates more than%. As bone mineral density decreases due to aging and / or disease, bone strength decreases and fractures are more likely to occur. The mineral content of human and animal bone can be accurately measured by dual energy X-ray absorption (DEXA), which can quantify changes of about 1%. DEXA can be used to assess changes in bone mineral density.

Adult osteoporosis Adult orchidectomized (ORX) rats can be used as a model for male osteoporosis.

Fifty male Sprague-Dawley rats undergo apparent surgery or orchiectomy at 10 months of age. Many rats can be necropsied at day 0 to provide a baseline control. ORX rats were treated with vehicle (10% ethanol in water) or an estrogen agonist / antagonist in combination with testosterone at various doses for 60
Treat for days (po daily). 10 mg / kg calcein 13 days and 3 days before necropsy in all rats
(Sigma Chemical Co., St. Louis, MO) is injected subcutaneously.

1) Total plasma cholesterol : Total plasma cholesterol is measured using a sensitive cholesterol colorimetric assay (Boehringer Mannheim Biochemicals, Indianapolis, IL).

2) Prostate weight : Prostate weight is measured immediately at autopsy. 3) Measurement of thigh bone mineral : Remove the right thigh from each rat, and use dual energy X-ray absorption method (DEXA, QDR
1000 / W, Hologic Inc., Waltham, Mass.]. Scanning area size is 5.08 × 1.902cm, resolution is 0.0254 × 0.0127c
m and the scanning speed is 7.25 mim / sec. The scanned image of the thigh is analyzed and the total thigh (WF), distal femoral metaphyseal (DF)
M), and bone area of the femoral shaft (FS), bone mineral content (B
MC) and bone mineral density (BMD) were determined as “HZ Ke et a
l., Droloxifene, a New Estrogen Antagonist / Agonis
t, Prevents Bone Loss in Ovariectomized Rats.Endo
Clinology 136; 2435-2441, 1995 ".

4) Histomorphometry of the third lumbar vertebra (LV3) : L
V3 was removed at necropsy, muscles were dissected, fixed in 70% ethanol, dehydrated in graded concentrations of ethanol, defatted in acetone, and then methyl methacrylate
(Eastman Organic Chemicals, Rochester, NY). Reichert-Jung Po
lycut S microtome) to extend the length of LV3
Cut to a thickness of μm and 10 μm. One 4μ from each rat
The m part and one 10 μm part are used in the cancellous bone histomorphometry. Stain 4 μm sections with denatured Masson's Trichrome stain,
The μm portion is not stained.

Using the Bioquant OS / 2 histomorphometry system (R & M Biometrics, Nashville, TN), the growth plate-epiphyseal junction was used.
The secondary spongioses of the proximal tibial metaphysis between 1.2 mm and 3.6 mm to the plate-epiphyseal junction
Perform a) static and dynamic tissue morphology measurement. The first 1.2 mm of the tibial metaphyseal area to limit the measurement to the second spongy mass
Must be excluded. Bone volume, using 4 μm pieces
Measure bone structure and bone resorption index,
Bone formation and bone turnover using 10 μm sections
Measure the index for

(A) Measurement of trabecular bone volume and structure
Calculations : 1. Total metaphyseal area (TV, mm ² ): metaphyseal area 1.2 mm to 3.6 mm distal to the growth plate-epiphyseal junction 2. Trabecular bone area (BV, mm ² ): TV The entire area of the trabeculae within 3. Trabecular bone perimeter (BS, mm): Length of all trabecular perimeters 4. Trabecular bone volume (BV / TV,%): BV / TV × 100 5 Number of trabecular bone (TBN, # / mm): 1.199 / 2 × BS / TV 6. Thickness of trabecular bone (TBT, μm): (2000 / 1.199) × (BV / BS) 7. Bone separation (TBS, μm): (2000 / 1.199) × (TV-BV) (B) Measurement and calculation of bone resorption : 1.Osteoclast cell count (OCN, #): Osteoclast in whole metaphyseal zone Total number of cells 2. Trabecular bone area (OCP, mm): Length of trabecular perimeter coated with osteoclasts 3. Osteoclast number / mm (OCN / mm, # / mm): OCN / BS 4. Percent osteoclast perimeter (% OCP,%): OCP / BS
× 100 (C) Measurement and calculation of bone formation and bone replacement : 1.A single calcein-labeled perimeter (SLS,
mm): Total length of trabecular perimeter labeled with one calcein label 2.Perimeter labeled with double calcein (DLS,
mm): Total length of trabecular perimeter labeled with two calcein labels 3.inter-labeled width (IL
V, μm): average distance between two calcein labels 4.Percent mineralized perimeter (PMS,%): (SLS / 2
+ DLS) / BS × 100 5. Mineral deposition rate (MAR, μm / day): ILW / label interval 6.Bone formation rate / surface ref. (BFR / BS, μm ² / d / μm): (SLS / 2
+ DLS) × MAR / BS 7. Bone replacement speed (BTR,% / y): (SLS / 2 + DLS) × MAR / BV × 10
0 5) 5th lumbar body compression test : Material test system (Materia
Mechanical testing is performed on the fifth lumbar vertebral body (LV5) using an l Testing System (Model 810, MTS Systems, Minneapolis, MN). Each test results in a load displacement curve. Procedure by Mosekilde et al. (Mosekilde
The mechanical properties of LV5 are measured using a compression test according to lde, L., et al., Endocrinol 1994; 134: 2126-2134). Using a 2.5 kN load cell (MTS model 661, 14A-03) at a displacement speed of 0.1 mm / s, LV5 (2
Excluding the two epiphyses, posterior pedicle arch, and spinous processes]. Calculate the maximum load and maximum stiffness from the load displacement curve.

Effect on Total Cholesterol Level The effect of the combination of an estrogen agonist / antagonist with testosterone on total cholesterol plasma levels is determined according to the following method. Treatment with combination (10-1000
Blood samples are collected by cardiac puncture from anesthetized (SD) 4-6 month old rats that have been treated with μg / kg / day, e.g., sc or orally for 28 days or with vehicle over the same time period, or have undergone apparent surgery. . 30 μl 5% E
Put the blood in a tube containing DTA (10 μl / ml of blood
EDTA). After centrifugation at 2500 rpm for 10 minutes at 20 ° C., the plasma is removed and stored at −20 ° C. until assay. Total cholesterol is assayed using a standard enzyme activity assay kit from Sigma Diagnostics.

Imaging and Analysis of Reactive Brachial Artery of the Brachial Artery The primary results for clinical studies were estrogen agonist /
Changes in endothelium-dependent vasodilator capacity in brachial arteries after 8 weeks of treatment with antagonist and testosterone or placebo. The vasodilator stimulus used is an increase in brachial artery flow caused by ischemic hyperemia in the distal limb. The change in diameter of the brachial artery is high resolution 2-
D ultrasonic system [automatic boundary detection algorithm (automate
The method measures the change in diameter based on image processing techniques designed to measure the diameter of the brachial artery using d boundary detection algorithms). Using standardized protocols for sample preparation, image acquisition, and image analysis, accurate and precise measurements of brachial artery diameter and wall thickness have been developed, demonstrated, and Used in research.

[0125] Participants should be in a supine position in a quiet room.
Rest for 10 minutes. A blood pressure measurement cuff is placed on the right forearm just below the anterior elbow fossa and the arm is supported by a sandbag so that the blood pressure measurement cuff can expand and contract within the range of arm movement. Measure blood pressure and heart rate with the left arm using an automatic sphygmomanometer. Once a reasonably stable position has been determined and the blood pressure has been measured, an image of the brachial artery at baseline is obtained (see the section "Image acquisition"). After baseline imaging, the blood pressure measurement cuff should be 30 mmHg above maximal blood pressure in 5 minutes.
Immediately inflates to high blood pressure. The brachial artery is imaged again, starting 30 seconds before the cuff pressure release and continuing for a total of 3 minutes after the cuff pressure release.

Image Acquisition Using a high resolution ultrasound system, the right upper arm artery is examined approximately 7 cm proximal to the elbow flexure. Record a short Doppler signal in the vein to confirm that it is the same. Once the transducer is carefully moved and the proximal and distal wall boundaries are imaged, the transducer is held in that position during the test. Careful observation of the surrounding tissue provides an internal landmark that confirms that this has been achieved. A baseline image is then recorded for about 2 minutes by a video tape recorder. During the 5-minute interval in which the right blood pressure measurement cuff is inflated 30 mmHg higher than the maximum blood pressure, the sonographer alternately looks at the B-mode image and the Doppler signal by a sonographer.
Confirm that a high-quality image is retained and that the blood flow in the vein changes significantly. Record high quality B-mode images during the last 30 seconds before rapid cuff deflation. Immediately after the cuff pressure release, record the Doppler signal for 10 to 15 seconds to obtain the peak flow (p
eak flow) and then continuously record high quality B-mode images.

[0127] Before performing the analysis analysis of the image, to fully review the video tape by the image analysis experts. After confirming the tape portion indicating the brachial artery at the baseline, the frame grabber (frame g
rabber) digitizes 30 frames into a 512 x 512 x 8 bit gray scale. Medial to the proximal and distal walls of the brachial artery using a semi-automatic boundary detection algorithm
-Place the adventitia border on the artery segment 2.0-2.5 cm in length. If the boundary points are clearly outside the true location of the medial-adventitia boundary, the boundary points in question are manually edited by an image analysis specialist. However, every effort is made to minimize such editing work. The mean diameter of the arteries is automatically calculated and the baseline diameter is determined using the mean diameter from the 3-D baseline frame. This same exact procedure is repeated to determine the diameter of the artery just before the cuff pressure release. A similar method is used to determine the maximum diameter that occurs 3 minutes after the cuff pressure release. The time from the cuff pressure release to the point of maximum inflation is also recorded.

Criteria for Primary and Secondary Results The criterion for primary results is the relative rate of change of the mean arterial diameter, calculated as (maximum diameter / baseline diameter) × 100. The time to maximum inflation and the rate of change from end of cuff occlusion to maximum inflation are also determined.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/4439 A61K 31/4439 31/4453 31/4453 31/453 31/453 31/4535 31/4535 31 / 4738 31/4738 31/55 31/55 45/00 45/00 A61P 3/06 A61P 3/06 5/06 5/06 5/16 5/16 5/30 5/30 5/32 5/32 9 / 10 9/10 15/08 15/08 15/10 15/10 15/12 15/12 19/02 19/02 19/10 19/10 21/02 21/02 43/00 123 43/00 123 F Terms (reference) 4C084 AA17 MA02 NA14 ZA36 ZA45 ZA81 ZA94 ZA97 ZC10 ZC11 ZC42 4C086 AA01 AA02 BC07 BC10 BC17 BC21 BC30 BC31 DA09 GA02 GA04 GA07 GA08 GA12 MA02 NA14 ZA36 ZA45 ZA81 ZA94 ZA97 ZCA MA4 NA206 ZA81 ZA94 ZC10 ZC11 ZC42

Claims (15)

[Claims] 1. A pharmaceutical composition for treating male menopause in a male patient, comprising administering to a male patient in need of treatment for male menopause a therapeutically effective amount of an estrogen agonist / antagonist and testosterone. 2. The method of claim 1, wherein said estrogen agonist / antagonist is of the formula I In the formulas, A is selected from CH ₂ and NR;. 1 to Y is to be independently selected from ^{(a) R 4; B,} D, and E are independently selected from CH and N Phenyl optionally substituted with 3 substituents; (b) naphthyl optionally substituted with 1 to 3 substituents independently selected from R ⁴ ; (c) independent from R ⁴ 1-2 may be substituted with a substituent C ₃ -C ₈ cycloalkyl that is selected; substituted with (d) one to two substituents independently selected from R ⁴ and good C ₃ -C ₈ cycloalkenyl; (e) -O -, - NR 2 -, and -S (O) _n - contains up to two heteroatoms selected from the group consisting of, R ⁴ May be substituted with 1 to 3 substituents independently selected from 5
Membered heterocycles containing up to two heteroatoms selected from the group consisting of (f) -O-, -NR ^2- , and -S (O) _n- , independently selected from R ⁴ 6 which may be substituted with 1 to 3 substituents
Or (g) a bicyclic ring system formed by condensing a 5- or 6-membered heterocyclic ring with a phenyl ring, wherein the heterocyclic ring is -O-,-
Containing up to two heteroatoms selected from the group consisting of NR ^2- , and -S (O) _n- , and substituted with 1-3 substituents independently selected from R ⁴ May be;
Z ¹ is (a)-(CH ₂ ) _p W (CH ₂ ) _q- ; (b) -O (CH ₂ ) _p CR ⁵ R ^6- ; (c) -O (CH ₂ ) _p W (CH ₂ ) _q- ; (d) -OCHR ² CHR ^3- ; or (e) -SCHR ² CHR ^3- ; G is (a) -NR ⁷ R ⁸ ; (b) Wherein n is 0, 1, or 2; m is 1, 2, or 3; Z ² is -NH-, -O-, -S-, or -CH _2- ; adjacent may be fused with one or two phenyl rings carbon atom, it may optionally be independently substituted with 1-3 substituents carbon atoms, and nitrogen atom, is selected from R ⁴ chemically suitable substituents may be independently substituted); wherein or (c) 5 to 12 carbon atoms, optionally combined crosslinked or condensed, 1 are independently selected from R ⁴ A bicyclic amine optionally substituted with up to 3 substituents; or Z ¹ and G
Is combined with W is (a) -CH _2- ; (b) -CH = CH-; (c) -O-; (d) -NR ^2- ; (e) -S (O) _n -; (f) (g) -CR ² (OH)-; (h) -CONR ^2- ; (i) -NR ² CO-; (j) Or (k) -C≡C-;; R is hydrogen or C ₁ -C ₆ alkyl; R ² and R ³ are independently (a) hydrogen; or (b) C ₁ -C ₄ alkyl; a is; R ⁴ is, (a) hydrogen; (b) halogen; (c) C ₁ -C ₆ alkyl; (d) C ₁ -C ₄ alkoxy; (e) C ₁ -C ₄ acyloxy; (f) C ₁ -C ₄ alkylthio; (g) C ₁ -C ₄ alkylsulfinyl; (h) C ₁ -C ₄ alkylsulfonyl; (i) hydroxy (C ₁ -C ₄ ) alkyl; (j) aryl ( C ₁ -C _{4) alkyl; (k) -CO 2 H;} (l) -CN; (m) -CONHOR; (n) -SO 2 NHR; (o) -NH 2; (p) C 1 -C ₄ alkylamino; (q) C ₁ -C _{4 dialkylamino; (r) -NHSO 2 R;} (s) -NO 2; (t) - aryl; or (u) -OH; a and; R ⁵ and R ⁶ is independently C ₁ -C ₈ alkyl, or together forms a C ₃ -C ₁₀ carbocycle and R ⁷ and R ⁸ are independently (a) phenyl; (b) saturated or C ₃ -C ₁₀ carbocyclic unsaturated; (c) -O -, - N-, and Haitai of up to 2 selected from -S- (D) H;; or (e) C ₁ -C ₆ alkyl; a either, or (f) together with R ⁵ or R ⁶ 3~8 C ₃ -C ₁₀ heterocyclic ring containing B atoms R ⁷ and R ⁸ in linear or cyclic form, up to three independently selected from C ₁ -C ₆ alkyl, halogen, alkoxy, hydroxy, and carboxy The ring formed by R ⁷ and R ⁸ may be fused to a phenyl ring; e is 0, 1, or 2; m is 1, 2 , Or 3; n is 0, 1, or 2; p
Is 0, 1, 2, or 3; and q is 0, 1, 2, or
3) or an optical isomer or geometric isomer of the compound; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or prodrug of the compound; Item 4. The pharmaceutical composition according to Item 1, 3. The method of claim 2, wherein the estrogen agonist / antagonist has the formula
(IA) [Wherein G is R ⁴ is H, OH, F, or Cl; B and E are CH
Or independently selected from N), or a compound or an optical isomer or geometric isomer of the compound; or a pharmaceutically acceptable salt of the compound, N-oxide,
2. The pharmaceutical composition according to claim 1, which is an ester, a quaternary ammonium salt, or a prodrug. 4. The method according to claim 1, wherein the estrogen agonist / antagonist is (-)
-Cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalen-2-ol or an optical isomer of said compound or A geometric isomer; or a pharmaceutically acceptable salt of the compound,
2. The pharmaceutical composition according to claim 1, which is an N-oxide, an ester, a quaternary ammonium salt, or a prodrug. 5. The pharmaceutical composition according to claim 4, wherein said estrogen agonist / antagonist is in the form of D-tartrate. 6. To treat gynecomastia, dyslipidemia, cardiovascular disease, atherosclerosis, hypogonadism, benign prostatic hyperplasia, or osteoporosis; or to increase libido; or male A pharmaceutical composition for maintaining or improving vascular reactivity in a patient, wherein the male patient requires treatment for the disorder,
A pharmaceutical composition for administering a therapeutically effective amount of an estrogen agonist / antagonist and testosterone. 7. The method of claim 1, wherein said estrogen agonist / antagonist is of the formula I In the formulas, A is selected from CH ₂ and NR;. 1 to Y is to be independently selected from ^{(a) R 4; B,} D, and E are independently selected from CH and N Phenyl optionally substituted with 3 substituents; (b) naphthyl optionally substituted with 1 to 3 substituents independently selected from R ⁴ ; (c) independent from R ⁴ 1-2 may be substituted with a substituent C ₃ -C ₈ cycloalkyl that is selected; substituted with (d) one to two substituents independently selected from R ⁴ and good C ₃ -C ₈ cycloalkenyl; (e) -O -, - NR 2 -, and -S (O) _n - contains up to two heteroatoms selected from the group consisting of, R ⁴ May be substituted with 1 to 3 substituents independently selected from 5
Membered heterocycles containing up to two heteroatoms selected from the group consisting of (f) -O-, -NR ^2- , and -S (O) _n- , independently selected from R ⁴ 6 which may be substituted with 1 to 3 substituents
Or (g) a bicyclic ring system formed by condensing a 5- or 6-membered heterocyclic ring with a phenyl ring, wherein the heterocyclic ring is -O-,-
Containing up to two heteroatoms selected from the group consisting of NR ^2- , and -S (O) _n- , and substituted with 1-3 substituents independently selected from R ⁴ May be;
Z ¹ is (a)-(CH ₂ ) _p W (CH ₂ ) _q- ; (b) -O (CH ₂ ) _p CR ⁵ R ^6- ; (c) -O (CH ₂ ) _p W (CH ₂ ) _q- ; (d) -OCHR ² CHR ^3- ; or (e) -SCHR ² CHR ^3- ; G is (a) -NR ⁷ R ⁸ ; (b) Wherein n is 0, 1, or 2; m is 1, 2, or 3; Z ² is -NH-, -O-, -S-, or -CH _2- ; adjacent may be fused with one or two phenyl rings carbon atom, it may optionally be independently substituted with 1-3 substituents carbon atoms, and nitrogen atom, is selected from R ⁴ chemically suitable substituents may be independently substituted); wherein or (c) 5 to 12 carbon atoms, optionally combined crosslinked or condensed, 1 are independently selected from R ⁴ Or a bicyclic amine optionally substituted with up to 3 substituents; or Z ¹ and G combine to form W is (a) -CH _2- ; (b) -CH = CH-; (c) -O-; (d) -NR ^2- ; (e) -S (O) _n -; (f) (g) -CR ² (OH)-; (h) -CONR ^2- ; (i) -NR ² CO-; (j) Or (k) -C≡C-;; R is hydrogen or C ₁ -C ₆ alkyl; R ² and R ³ are independently (a) hydrogen; or (b) C ₁ -C ₄ alkyl; a is; R ⁴ is, (a) hydrogen; (b) halogen; (c) C ₁ -C ₆ alkyl; (d) C ₁ -C ₄ alkoxy; (e) C ₁ -C ₄ acyloxy; (f) C ₁ -C ₄ alkylthio; (g) C ₁ -C ₄ alkylsulfinyl; (h) C ₁ -C ₄ alkylsulfonyl; (i) hydroxy (C ₁ -C ₄ ) alkyl; (j) aryl ( C ₁ -C _{4) alkyl; (k) -CO 2 H;} (l) -CN; (m) -CONHOR; (n) -SO 2 NHR; (o) -NH 2; (p) C 1 -C ₄ alkylamino; (q) C ₁ -C _{4 dialkylamino; (r) -NHSO 2 R;} (s) -NO 2; (t) - aryl; or (u) -OH; a and; R ⁵ and R ⁶ is independently C ₁ -C ₈ alkyl, or together forms a C ₃ -C ₁₀ carbocycle and R ⁷ and R ⁸ are independently (a) phenyl; (b) saturated or C ₃ -C ₁₀ carbocyclic unsaturated; (c) -O -, - N-, and Haitai of up to 2 selected from -S- (D) H;; or (e) C ₁ -C ₆ alkyl; a either, or (f) together with R ⁵ or R ⁶ 3~8 C ₃ -C ₁₀ heterocyclic ring containing B atoms R ⁷ and R ⁸ , in linear or cyclic form, up to three independently selected from C ₁ -C ₆ alkyl, halogen, alkoxy, hydroxy, and carboxy The ring formed by R ⁷ and R ⁸ may be fused to a phenyl ring; e is 0, 1, or 2; m
Is 1, 2, or 3; n is 0, 1, or 2; p is
Is 0, 1, 2, or 3; and q is 0, 1, 2, or 3
Or an optical isomer or geometric isomer of the compound; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or prodrug of the compound; 6. The pharmaceutical composition according to 6. 8. The method of claim 8, wherein the estrogen agonist / antagonist has the formula
(IA) Wherein G is R ⁴ is H, OH, F, or Cl; B and E are CH
Or independently selected from N), or a compound or an optical isomer or geometric isomer of the compound; or a pharmaceutically acceptable salt of the compound, N-oxide,
7. The pharmaceutical composition according to claim 6, which is an ester, a quaternary ammonium salt, or a prodrug. 9. The method according to claim 9, wherein the estrogen agonist / antagonist is (-)
-Cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalen-2-ol or an optical isomer of said compound or A geometric isomer; or a pharmaceutically acceptable salt of the compound,
7. The pharmaceutical composition according to claim 6, which is an N-oxide, an ester, a quaternary ammonium salt, or a prodrug. 10. The method wherein the estrogen agonist / antagonist is D-
10. The pharmaceutical composition according to claim 9, which is in the form of a tartrate. 11. Menopause, gynecomastia, dyslipidemia,
To treat heart disease, atherosclerosis, hypogonadism, benign prostatic hyperplasia, or osteoporosis;
Or for increasing libido; or a kit for maintaining or improving vasoreactivity in male patients, comprising: a) one or more pharmaceutical compositions comprising an estrogen agonist / antagonist and testosterone; And b) menopause, gynecomastia, dyslipidemia, cardiovascular disease,
Administer the pharmaceutical composition to treat atherosclerosis, hypogonadism, benign prostatic hyperplasia, or osteoporosis, or to increase libido, or to maintain or improve vascular reactivity in male patients The kit comprising: instructions for using the kit. 12. The estrogen agonist / antagonist,
Formula I In the formulas, A is selected from CH ₂ and NR;. 1 to Y is to be independently selected from ^{(a) R 4; B,} D, and E are independently selected from CH and N Phenyl optionally substituted with 3 substituents; (b) naphthyl optionally substituted with 1 to 3 substituents independently selected from R ⁴ ; (c) independent from R ⁴ 1-2 may be substituted with a substituent C ₃ -C ₈ cycloalkyl that is selected; substituted with (d) one to two substituents independently selected from R ⁴ and good C ₃ -C ₈ cycloalkenyl; (e) -O -, - NR 2 -, and -S (O) _n - contains up to two heteroatoms selected from the group consisting of, R ⁴ May be substituted with 1 to 3 substituents independently selected from 5
Membered heterocycles containing up to two heteroatoms selected from the group consisting of (f) -O-, -NR ^2- , and -S (O) _n- , independently selected from R ⁴ 6 which may be substituted with 1 to 3 substituents
Or (g) a bicyclic ring system formed by condensing a 5- or 6-membered heterocyclic ring with a phenyl ring, wherein the heterocyclic ring is -O-,-
Containing up to two heteroatoms selected from the group consisting of NR ^2- , and -S (O) _n- , and substituted with 1-3 substituents independently selected from R ⁴ May be;
Z ¹ is (a)-(CH ₂ ) _p W (CH ₂ ) _q- ; (b) -O (CH ₂ ) _p CR ⁵ R ^6- ; (c) -O (CH ₂ ) _p W (CH ₂ ) _q- ; (d) -OCHR ² CHR ^3- ; or (e) -SCHR ² CHR ^3- ; G is (a) -NR ⁷ R ⁸ ; (b) Wherein n is 0, 1, or 2; m is 1, 2, or 3; Z ² is -NH-, -O-, -S-, or -CH _2- ; adjacent may be fused with one or two phenyl rings carbon atom, it may optionally be independently substituted with 1-3 substituents carbon atoms, and nitrogen atom, is selected from R ⁴ chemically suitable substituents may be independently substituted); wherein or (c) 5 to 12 carbon atoms, optionally combined crosslinked or condensed, 1 are independently selected from R ⁴ A bicyclic amine optionally substituted with up to 3 substituents; or Z ¹ and G
Is combined with W is (a) -CH _2- ; (b) -CH = CH-; (c) -O-; (d) -NR ^2- ; (e) -S (O) _n -; (f) (g) -CR ² (OH)-; (h) -CONR ^2- ; (i) -NR ² CO-; (j) Or (k) -C≡C-;; R is hydrogen or C ₁ -C ₆ alkyl; R ² and R ³ are independently (a) hydrogen; or (b) C ₁ -C ₄ alkyl; a is; R ⁴ is, (a) hydrogen; (b) halogen; (c) C ₁ -C ₆ alkyl; (d) C ₁ -C ₄ alkoxy; (e) C ₁ -C ₄ acyloxy; (f) C ₁ -C ₄ alkylthio; (g) C ₁ -C ₄ alkylsulfinyl; (h) C ₁ -C ₄ alkylsulfonyl; (i) hydroxy (C ₁ -C ₄ ) alkyl; (j) aryl ( C ₁ -C _{4) alkyl; (k) -CO 2 H;} (l) -CN; (m) -CONHOR; (n) -SO 2 NHR; (o) -NH 2; (p) C 1 -C ₄ alkylamino; (q) C ₁ -C _{4 dialkylamino; (r) -NHSO 2 R;} (s) -NO 2; (t) - aryl; or (u) -OH; a and; R ⁵ and R ⁶ is independently C ₁ -C ₈ alkyl, or together forms a C ₃ -C ₁₀ carbocycle and R ⁷ and R ⁸ are independently (a) phenyl; (b) saturated or C ₃ -C ₁₀ carbocyclic unsaturated; (c) -O -, - N-, and Haitai of up to 2 selected from -S- (D) H;; or (e) C ₁ -C ₆ alkyl; a either, or (f) together with R ⁵ or R ⁶ 3~8 C ₃ -C ₁₀ heterocyclic ring containing B atoms R ⁷ and R ⁸ , in linear or cyclic form, up to three independently selected from C ₁ -C ₆ alkyl, halogen, alkoxy, hydroxy, and carboxy The ring formed by R ⁷ and R ⁸ may be fused to a phenyl ring; e is 0, 1, or 2; m
Is 1, 2, or 3; n is 0, 1, or 2; p is
Is 0, 1, 2, or 3; and q is 0, 1, 2, or 3
Or an optical or geometric isomer of the compound; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or prodrug of the compound; The kit according to 11. 13. The estrogen agonist / antagonist,
Formula (IA) Wherein G is R ⁴ is H, OH, F, or Cl; B and E are CH
Or independently selected from N), or a compound or an optical isomer or geometric isomer of the compound; or a pharmaceutically acceptable salt of the compound, N-oxide,
12. The kit according to claim 11, which is an ester, a quaternary ammonium salt, or a prodrug. 14. The estrogen agonist / antagonist,
(-)-Cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalene-2-
All or an optical or geometric isomer of the compound; or a pharmaceutically acceptable salt of the compound,
12. The kit according to claim 11, which is an N-oxide, an ester, a quaternary ammonium salt, or a prodrug. 15. The method wherein the estrogen agonist / antagonist is D-
15. The kit according to claim 14, which is in the form of a tartrate.